FR2761985A1 - NOVEL AMINO COMPOUNDS OF 6,7,8,9-TETRAHYDRO-CYCLOPENTA [A] NAPHTHALENE AND 2,3-DIHYDRO-CYCLOPENTA [E] INDENE, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME - Google Patents

Abstract

Novel amino compounds of the formula: (FRICTION IN BOPI) wherein n and Y are as defined in the description, in racemic form or optical isomers, and their addition salts with pharmaceutically acceptable acids.These compounds may be used as medicines.

Description

The present invention relates to novel amino compounds of 6,7,8,

9-tetrahydro-

  cyclopenta [a] naphthalene and 2,3-dihydro-cyclopenta [e] indene, their method of preparation and

  the pharmaceutical compositions which contain them.

  It relates more particularly to the compounds of formula I:

CH2-CH23-CH

N.Y.

O

  wherein: - n represents zero or one; and Y represents a hydrogen atom or a radical chosen from those corresponding to the formulas: R 3 -CH 2 W - (CH 2) n and - (CH 2) m -NH-C

R2 R

  in which: - W represents a hydrogen atom or an alkyl, alkenyl or alkynyl radical each having from 1 to 5 carbon atoms in straight or branched chain, - p represents an integer from 1 to 5 inclusive, - Ri and R2 , identical or different, each represent a hydrogen or halogen atom or a hydroxy, (C 1 -C 5) alkoxy, -NH-SO 2 -CH 3, -NH-SO 2 -CF 3, -NH-CO-CH 3, R radical - CN / Ra -NH-CO-CF3 or R5 RO in which R4 and Rs, identical or different, each represent a hydrogen atom or a radical (C1-C6) alkyl chain straight or branched - m represents a number integer from 2 to 5 inclusive and - R3 represents a hydrogen or halogen atom or a hydroxy, (C] -C6) alkoxy, trifluoromethyl, cyano or phenyl radical; in racemic form or optical isomers and their addition salts with an acid

pharmaceutically acceptable.

  The compounds of formula I act as potent dopaminergic ligands both in vitro and in vivo. Among the five subtypes D1 to D5 of known dopaminergic receptors, the compounds of the present invention are more specific with respect to the receptor subtype.

dopaminergic D3.

  Currently, substances used therapeutically for the treatment of conditions in which the dopaminergic system is involved all strongly bind to the D2 receptor subtype, whether they are dopaminergic blockers (used in diseases attributable to hyperactivity of this neurotransmitter, as for example in schizophrenia and psychotic disorders) or dopaminergic activators (used in diseases attributable to the hypoactivity of this neurotransmitter, as for example in Parkinson's disease). However, these D2 dopaminergic blockers or activators have numerous side effects: tardive dyskinesia, hyperprolactinemia, amenorrhea

  first, cardio-vascular effects and engines for the second.

  D3 receptors, whose concentrations are very important in the limbic system, but in contrast to the very weak D2 receptors in the nigrostriatal nucleus and in the lactotrophic cells, therefore constitute a preferred site of action for molecules that are active at the level of the dopaminergic system. . The molecules acting preferentially at the dopaminergic D3 receptors, as is the case with the compounds of the present invention, are therefore free of the side effects typically associated with the ligands of the D2 receptors,

as mentioned previously.

  Indeed, studies carried out in vitro (binding on dopaminergic receptors cloned human) with the compounds of the present invention show that they act as

  high affinity ligands at dopamine D3 receptors.

  This specificity of action gives the compounds of the present invention a very particular interest for their use as a drug acting at the level of the system.

  dopaminergic, especially in Parkinson's disease (J. Neur., Transm., 1993, 94, 1-

  19), memory disorders (Nature, 1990, 347, 146-151), drug abuse (Science, 1993,

  260, 1814), depression, schizophrenia and psychoses.

  The present invention also relates to pharmaceutical compositions containing as active principle a compound of formula I or a physiologically tolerable salt thereof

  mixed or combined with one or more suitable pharmaceutical excipients.

  The pharmaceutical compositions thus obtained are generally in metered form containing from 0.5 to 25 mg of active principle. They may, for example, take the form of tablets, dragees, capsules, suppositories, injectable or drinkable solutions and be

  administered orally, rectally or parenterally according to the forms used.

  The dosage varies according to the age and weight of the patient, the route of administration and the treatments

  associated and ranges from 0.5 to 25 mg of active ingredient, one to three times a day.

  The subject of the present invention is also the process for the preparation of the racemic or optically active compounds of formula I, characterized in that a tertiary amine of formula II is reacted:

 CH2-CH2-CH3

  Wherein X is a halogen atom selected from bromine and iodine and has the previously defined meaning with butyllithium and dimethylformamide in tetrahydrofuran to obtain an aldehyde. of formula III:

CH2-CH2-CH3

  in which n has the previously defined meaning, which is treated with malonic acid in pyridine in the presence of piperidine, to yield a compound of formula IV:

CH2-CH2-CH

NTC ZCH_ (IV)

  HO2C) n wherein n has the previously defined meaning, which is hydrogenated in the presence of palladium on charcoal, to give an acid of formula V:

CH2-CH2-CH3

2 3

H V)

  HO2C) n wherein n has the previously defined meaning, which is cyclized by means of polyphosphoric acid under heat to yield a compound of formula I ':

CH2-CH2-CH3

- H (I ')

  where n has the previously defined meaning, which is treated with a compound of formula VI: Hal-Y, (VI) in which Hal is a halogen atom selected from chlorine, bromine and iodine atoms and Y, takes on the meaning of Y with the exception of the hydrogen value to yield a compound of formula I ":

CH2-CH2-CH3

YN1Y (I ")

  Where n has the previously defined meaning and Y, has the meaning of Y at

  except for the hydrogen value.

  All of the compounds I 'and IU "constitute all the compounds of formula I. If desired, from the racemic mixtures, the optical isomers are prepared according to

  classical methods of literature.

  The salts of the compounds of formula I with pharmaceutically acceptable acids were obtained according to standard methods as indicated in the examples below. The raw materials are either known products or products obtained from known substances, according to methods known from the literature. The following examples, given in a non-limiting manner, illustrate the present invention. Dots

  melting was determined on the Kofler heating stage under a microscope.

  EXAMPLE 1 (7-R, S) 7- (N-propylamino) -6,7,8,9-tetrahydro-cyclopenta [naphthalenol]

  1-one and its hydrochloride Step 1: (7 R, S) 3-Formyl-7- (N-benzyl-N-propylamino) -5,6,7,8-tetrahydronaphthalene

  19.5 g (0.0544 mol) of (7 R, S) 3-bromo-7- (N-benzyl N -propylamino) -5,6,7,8

  tetrahydronaphthalene are dissolved in 0.243 l of tetrahydrofuran and cooled to -

    C. At this temperature, 51 ml of a 1.6 M solution of butyllithium in tetrahydrofuran is poured. After 2 hours after the end of the casting, a solution of 12.3 ml of dimethylformamide in 28 ml of tetrahydrofuran is added at this temperature. After one hour at -65 C we leave at room temperature for a weekend. It is taken up in water and with ether, decanted, dried and evaporated to obtain 16.3 g of an oil which corresponds to the expected product. (Yield = 93%) Step 2: 3 - [(7R, S) 7- (N-benzyl-N-propylamino) -5,6,7,8-tetrahydronaphthalen-3-yl] propenoic acid 6.9g ( 0.022 mole) of the compound obtained in the preceding stage, 11.3 g (0.045 mole) of malonic acid, 2.22 ml (0.022 mole) of piperidine and 82.7 ml of pyridine are fed for three hours.

  at 90 C, then 2 hours at reflux. It is left overnight at room temperature and concentrated.

  It is taken up in N hydrochloric acid and methylene chloride, decanted, dried over MgSO 4 and evaporated to obtain 8 g of crystals melting at 196 ° C. and corresponding to the expected product. Step 3: 3- [(7 R, S) -7- (N-propylamino) -5,6,7,8-tetrahydronaphthalen-3-yl] propionic acid 0.8 g of the compound obtained in the preceding stage, 1 g of formate d ammonium, 0.3 g of 10% Pd / C and 25 ml of methanol are refluxed for 4 hours. After filtration, the reaction medium is concentrated to obtain 0.4 g of a pink solid which melts at 155 ° C. and corresponds to the expected product. (Yield = 74%) Stage 4: title product 3g of the compound obtained in the preceding stage are added all at once in 30 ml of polyphosphoric acid preheated to 75 ° C. The temperature then rises to 92 ° C. keep one hour at this temperature. The heating is turned off and the temperature is lowered to 45 C and poured on ice. Basified with concentrated sodium hydroxide and extracted with ethyl acetate. After drying and evaporation, 1.4 g of an oil are obtained which is purified by H.P.L.C. using a nucleoprep 100-20 column, the mobile phase consisting of a mixture of CH2Cl2 / C2H50H / CF3CO2H in the ratio 100/5/1. 0.73 g of expected product is obtained (yield = 26.6%) which is converted into hydrochloride.

  with hydrochloric ether. P.F. of the expected hydrochloride: 260-264 C.

  EXAMPLE 2 (7 RS) 7- (N, N-dipropylamino) -6,7,8,9-tetrahydro-cyclopenta [a] naphthalen-1-one and its hydrochloride

  141 mg (0.58 mmol) of the title compound of Example I are dissolved in 8.4 ml of acetonitrile.

  0.41 g (3 mmol) of anhydrous K 2 CO 3 and 0.3 ml (3 mmol) of propyl iodide are then added. It is stirred at room temperature for 48 hours. The solvent is evaporated and then taken up in 1N sodium hydroxide and ethyl acetate. The organic phase is washed neutral and dried over MgSO 4 and then evaporated to yield the expected product, which is treated with hydrochloric ether to give 40 mg of hydrochloride. Mp> 260 C

(Yield = 21.5%).

  EXAMPLE 3 (7 R) 7- {N-propyl N- [4- (o-trifluoromethylbenzamido) butyl aminol]

  6.7.8.9-tetrahydro-cyclopenta [a] naphthalen-1-one and its hydrochloride To a solution of 0.7 g (2.9 mmol) of the title compound of Example 1 in 50 ml of methyl isobutyl ketone is added 2 g ( 15 mmol) of anhydrous K2CO3 and 1,11 (3,5 mmol) of N- (4-bromobutyl) o-trifluoromethylbenzamide. The mixture is heated at 75 ° C. for 12 hours and then, after cooling, the solvent is evaporated off, taken up in water and methylene chloride, decanted, dried over MgSO 4, evaporated to obtain an oil which is treated with ether

  hydrochloric acid to give 0.68 g of the expected product hydrochloride.

  By operating in the same way as in Example 3, the compounds which are the subject of the following examples were prepared:

  EXAMPLE 4 (7 R) 7- {N-propyl-N- [4- (o-fluorobenzamido) butyllamino} 6. 7.8.9-

  tetrahydro-cyclopenta [al naphthalen-1-one

  EXAMPLE 5 (7 R) 7- {N-propyl-N- [3- (o-methoxybenzamido) provpyllamino} 6.7.8.9-

  tetrahydro-cyclopenta [al naphthalen-1-one

  EXAMPLE 6 (7 RS) 7- {N-propyl-N- [3- (o-bromobenzamido) propylamino} 6,7,8,9

  tetrahydro-cyclopenta [al naphthalen-1-one EXAMPLE 7: Pharmacological study The selectivity for D3 receptors with respect to D2 receptors has been demonstrated:

  In vitro: by the D2 and D3 receptor binding technique.

  In vivo: by the ability of the products of the invention to modulate the hypothermia induced in the rat by the dopaminergic agonist D3: 7-OH-DPAT. (cf .: M. J. Millan et al.,

  J. Pharmacol. Exp. Ther., 1995, 275, 885).

  In vitro: study of the binding to human D, and D3 cell culture receptors CHO (Chinese Hamster Ovary) cells were stably transfected by the gene encoding the human dopamine D2 or D3 receptor according to the known methods of Literature. Native cells are deficient in DHFR enzyme (DiHydroFolate Reductase). These cells are cultured in an oven at 37 ° C. in a humid atmosphere of 5% CO2 and 95% air. Transfections were performed using Lipofectin (Gibco). The CHO cells cotransfected with the human D2 receptor and the phleomycin resistance gene were selected for their resistance to the presence of this antibiotic in the culture medium. Cells transfected with the human D3 receptor were selected in hypoxanthine / thymidine-free medium in the presence of methotrexate. The composition of the culture media used is for CHO-D2: DMEM (Dulbecco's Modified Eagle Medium) supplemented with 10% fetal calf serum and hypoxanthine / thimidine and for CHO-D3: DMEM supplemented with 10% of serum fetal calf dialyzed. The cells are harvested at confluence and the membranes

are then prepared.

  Membrane preparation After a few minutes in the presence of 0.2% trypsin, the cells are recovered and centrifuged at 2000 g for 5 minutes. The cell pellet, resuspended in buffer

  10 mM Tris-HCl pH 7.5 containing 5 mM MgSO 4 was then passed to Polytron.

  The homogenate is then centrifuged at 50,000 g for 15 minutes, and the pellet is resuspended by gentle sonication in the incubation buffer of composition: 50 mM tris-HCl, pH 7.5 containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 5 mM MgCl2. The membranes are then aliquoted and stored at -80 ° C until the day of the experiment. 5. Binding Experiments Incubations were performed in polypropylene tubes for a final volume of 400 gl containing: [25 I] -iodosulpride gl (Amersham)

  at 0.1 and 0.2 nM for the D2 and D3 receptors respectively.

  100 μl of buffer (total tubes) or 100 μl of 10 μM raclopride (nonspecific binding) or 100 μl of membrane preparation compound gl containing the D2 or D3 receptors, in

  buffer supplemented with 0.2% BSA (Bovine Serum Albumin).

  The concentration ranges of each compound have at least seven points

  determined in triplicate, each experiment is repeated at least twice.

  The incubation, which lasts thirty minutes at 30 ° C., is stopped by rapid filtration on Brandle apparatus, followed by three consecutive rinses with Tris-HCl buffer pH 7.4 containing 120 mM NaCl. The recovered filters are then counted on the counter

gamma.

  Analysis of the results The IC50 representing the concentration giving 50% inhibition of radioligand binding

  is calculated by nonlinear regression (Prism Graph method).

  The value of Ki is derived from the formula Ki = IC50 / (I + L / Kd) where L is the concentration of [125 I] -iodosulpride used in the experiment and Kd is its dissociation constant. The

  Results are expressed as pKi (pKi = -logKi).

  For the human D2 and D3 receptors, the Kd are respectively equal to 0.5 and 1.31 nM.

  In vivo: hypothermia in rats The tests were performed on male Wistar rats of 200-250g placed in individual cages with free access to food and water. The products were solubilized in distilled water, to which several drops of lactic acid were added. Injections were made in a volume of 1.0 ml / kg subcutaneously. Doses are expressed in terms of base. The rectal temperature of the rats was recorded using a digital thermistoprobe (Millan et al., J.P.E.T., 1993, 264, 1364-1376). In a first step, the rats were injected with the test compound or the vehicle and then returned to their cages for thirty minutes. Then the rats were injected with 7-OH-DPAT (0.16mg / kg) and returned to their cages. Thirty minutes later, the rectal temperature was measured and the difference was determined with respect to the basal values (AT C). Inhibitory Dose (95% Confidence Limits) to reduce to 50% the effect of 7-OH-DPAT was calculated according to the method of Finney (Statistical Method in Biological Assays, 2nd ed., Hafner publishing, New York,

1964).

  Results The products of the invention have a very good affinity for the D3 receptor. As

  for example the compound of Example 2 with a pKi of 8.0.

  In addition, the products of the invention all show a selectivity towards the D 2 receptor

greater than a factor of 10.

he

Claims (5)

  1) The amine compounds of formula I: CH2-CH2-CH3 N y ..   (I) wherein: - n represents zero or one; and Y represents a hydrogen atom or a radical chosen from those corresponding to the formulas: -CH 2 W - (CH 2) and - (CH 2) m -NH-CJ in which: W represents a hydrogen atom or an alkyl radical; , alkenyl or alkynyl each having from 1 to 5 carbon atoms in straight or branched chain, - p represents an integer from 1 to 5 inclusive, - Ri and R2, identical or different, each represent a hydrogen atom or halogen or hydroxy, (Ci-C5) alkoxy, -NH-SO2-CH3, -NH-SO2-CF3, -NH-CO-CH3, R4 --C - N   In which R4 and R5, which may be identical or different, each represent a hydrogen atom or a (C1-C6) alkyl radical in the straight or branched chain; m represents an integer of 1 to 5 carbon atoms; 2-5 inclusive and - R3 represents a hydrogen or halogen atom or a hydroxy, (C1-C6) alkoxy, trifluoromethyl, cyano or phenyl radical; in racemic form or optical isomers and their addition salts with an acid pharmaceutically acceptable.   2) A compound of claim 1 which is (7 R, S) 7- (N, Ndipropylamino) -6,7,8,9-   tetrahydro-cyclopenta [a] naphthalen-1-one and its hydrochloride.   3) A compound of claim 1 which is (7 R, S) 7- {N-propyl N- [4 (o-trifluoromethylbenzamido) butyl] amino} -6,7,8,9-tetrahydro-cyclopenta [ a] naphthalen-1-one and its hydrochloride. 4) The process for the preparation of the racemic or optically active compounds of claim 1, characterized in that a tertiary amine of formula II is reacted: CH2-CH2-CH   Xf C .....-% ,,. Wherein X is a halogen atom selected from bromine and iodine and n has the meaning previously defined with butyllithium and dimethylformamide in tetrahydrofuran to provide an aldehyde of formula III: CH2-CH2-CH3   OHC wherein n has the previously defined meaning, which is treated with malonic acid in pyridine in the presence of piperidine, to yield a compound of formula IV: CH2-CH2-CH HOC ", N CH 24 (IV)   HO2C) n wherein n has the previously defined meaning, which is hydrogenated in the presence of palladium on charcoal, to give an acid of formula V: CH2-CH2-CH3 NH (V)   HO2C wherein n has the previously defined meaning, which is cyclized by means of polyphosphoric acid under heat to yield a compound of the formula: CH2-CH2-CH 3   where n has the previously defined meaning, which is treated with a compound of formula VI: Hal-Y, (VI) in which Hal is a halogen atom selected from chlorine, bromine and iodine atoms and Y, takes on the meaning of Y with the exception of the hydrogen value to yield a compound of formula I ": CH2-CH2-CH3 1 2 (I ") )not 0   in which n has the previously defined meaning and Y, has the meaning of Y with the exception of the hydrogen value, and if desired, from the racemic mixtures, the optical isomers are prepared according to the standard methods of the literature, and the compounds of formula I are converted into their addition salts with acids pharmaceutically acceptable.   5) The pharmaceutical compositions, usable in the treatment of Parkinson's disease, memory disorders, disorders related to drug abuse, depression, schizophrenia and psychoses, containing as active ingredient a   compound according to any one of claims 1 to 3, with one or more excipients appropriate pharmaceutical products.